Cosmetic use of botulinum toxin for treatment of downturned mouth

ABSTRACT

This invention provides the use of  Botulinum  toxin (BTX) to cause paralysis of a depressor anguli oris (DAO) musculature in a patient to alleviate downturn at corners of the patient&#39;s mouth.

FIELD OF THE INVENTION

This invention relates to cosmetic uses of neuroparalytic toxins.

BACKGROUND OF THE INVENTION

Marionette lines are cosmetic defects of the human face often caused bya loss of dermal collagen in the lower lips and chin area as a result ofaging. These lines are usually accompanied by a downturn at the cornersof the mouth, producing a “sad” appearance, hence the term “sad mouth”.In this condition, the horizontal symmetry of the mouth is offset in adownward or inferior direction as a result of the downturn at thecorners of the mouth.

Some facial wrinkles and unsightly facial expressions are due tooveractivity of the underlying facial musculature. Neuroparalytic toxinshave been used for treatment of wrinkles and in other treatments forfacial rejuvenation. A toxin capable of blocking neuromuscular activityis administered to a facial muscle responsible for the facial defect orlesion. Resulting paralysis of the facial muscle alleviates the facialdefect. The preferred toxin for cosmetic use is Botulinum toxin (BTX).

BTX, produced by the bacterium Clostridium botulinum reversiblyparalyzes striated muscle when administered in sub-lethal doses. BTX hasbeen used in the treatment in a number of neuromuscular disorders andconditions involving muscular spasm including various forms of dystonia,hemifacial spasm, tremor, spasticity (e.g. resulting from Multiplesclerosis), anal fissures and various ophthalmologic conditions (c.f. A.Carruthers et al (1996), Botulinum A Exotoxin Use in ClinicalDermatology; Journal of the American Academy of Dermatology 34:788-797).

BTX is a generic term covering a family of toxins produced by C.botulinum comprising up to eight serologically distinct forms (A, B, C₁,C₂, D, E, F and G). These toxins which are among the most powerfulneuroparalytic agents known (c.f. Melling, J. et al (1988) ClostridiumBotulinum: Nature and Preparation for Clinical Use; Eye 2: 16-23).Serotypes A, B and F are the most potent. The mode of action is toinhibit the release of acetylcholine by the presynaptic nerve.

BTX-A serotype is available commercially under the trademarks BOTOX™(Allergan, Inc., Irvine, Calif., U.S.A.) and DYSPORT™ (SpeywoodPharmaceuticals, Ltd., Maidenhead, U. K.). The initial cosmetic use ofBTX was for treatment of forehead frown lines as reported in J.Carruthers and A. Carruthers (1992) “Treatment of Glabellar Frown Lineswith C. Botulinum-A Exotoxin”; J. Dermatol. Surge Oncol. 18: 17-21.Subsequently, various facial treatments employing BTX have been reportedbut use of BTX for treatment of midfacial defects has been limited.

Application of BTX near the mouth has been limited to treatment ofneuromuscular disorder. For example, hemifacial spasm has been treatedby BTX injection to the zygomaticus muscle but the modeolus adjacent thecorner of the mouth is avoided (J. Carruthers and A. Carruthers (1996)Botulinum A Exotoxin in Clinical Ophthalmology; Can. J. Ophthalmol. 31:389-400).

It has been reported that BTX injection to a group of muscles on oneside of a patient's face has been used to treat facial synkinesis andvertical asymmetry caused by facial nerve palsy (Armstrong, M .W. J. etal. (1996) “Treatment of Facial Synkinesis and Facial Asymmetry withBotulinum Toxin Type A Following Nerve Palsy”, Clin. Otolaryngol.21:15-20). In the latter procedure, the levator anguli oris, zygomaticusmajor, rizorius and depressor anguli oris muscles associated with themouth together with various muscles associated with the eye on thenormal side of a patient's face were all treated as a group in order toaffect the entire vertical symmetry of a patient's face to compensatefor effects of nerve palsy on the untreated side of the face.

While BTX treatment of the platysma muscle has been performed fortreatment of neck lines and banding, it has also been noted thatinjection of BTX into the platysma produces an uplift of the mouth (F.S. Brandt and B. Bellman (1998) Cosmetic Use of Botulinum A Exotoxin forthe Aging Neck; Dermatol. Surg. 24: 1232-1234). Injection of BTX intothe point of the chin has also been done for treatment of prominentmental crease (A. Carruthers and J. Carruthers; “Cosmetic Uses ofBotulinum A Exotoxin”; In: James, W. D. et al Eds. Advances inDermatology (1997) Mosby-Yearbook, Chicago: at pages 325-48).

The inventors have now found that “sad mouth” may be treated bysimultaneous bilateral BTX injection to depressor anguli oris(triangularis) muscle (termed herein DAO) thereby affecting thehorizontal symmetry of the mouth, without embarrassment to theappearance and function of the mouth. The normal function of thepatient's lips is not impeded.

SUMMARY OF THE INVENTION

This invention provides the use of Botulinum toxin (BTX) to causeparalysis of a depressor anguli oris (DAO) musculature in a patient toalleviate downturn at corners of the patient's mouth.

This invention provides A method of alleviating downturn of corners of apatient's mouth comprising:

a) locating a depressor anguli oris (DAO) muscle adjacent each corner ofsaid mouth; and

b) injecting into a DAO adjacent each corner of the mouth, a quantity ofBotulinum toxin (BTX) sufficient to cause paralysis of a DAO.

In this invention, BTX is simultaneously injected into each DAO adjacenteach corner of the patient's mouth. By simultaneously, it is meant thatthe injection into each DAO occurs as part of the same treatment,although a DAO on one side of the mouth may be selected for injectionbefore the other DAO during a treatment session.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: is a frontal view showing musculature of the human face andneck.

FIG. 2: is a frontal view of a human face and neck showing the generallocation of the DAO muscles and sites for BTX injection according tothis invention.

DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION

The term “BTX” as used herein includes any neurotoxin produced by C.botulinum or derivatives thereof. Preferably, the neurotoxin will be theBotulinum-A exotoxin, termed herein “BTX-A”.

The term “Unit equivalents” as used herein, is an amount of BTX which isequivalent to standard Units of BTX-A. A standard Unit of BTX-A isdefined as the mean LD₅₀ for female Swiss Webster mice weighing 18-20grams (E. J. Schantz and D. A. Kaultner (1978) Standardized Assay forClostridium botulinum Toxins; J. Assoc. Anal. Chem. 61: 96-99). Theestimated human LD₅₀(for a 70-kg person is 40 Units/kg or about2500-3000 Units.

BOTOX™ is sold in 100 Unit vials. DYSPORT™ is sold in 500 Unit vials.For cosmetic uses, the vial contents are typically diluted 1 or 2 ml ofwith sterile saline solution, which for BOTOX™ provides a 100 or 50Unit/ml dilution. DYSPORT™ BTX-A is roughly tenfold less toxic thanBOTOX™ and approximately fourfold greater amounts of the DYSPORT™product will usually be injected to achieve the same result as would isobtained using a specific number of Units of BOTOX™.

Commercially available toxin is typically freeze dried and is storedfrozen (e.g. at −4° C.) until ready for use. The toxin is diluted justprior to use. The resulting solution should be used within several hoursof preparation. Care should be taken to avoid foaming of the solution byslowing the entry of saline into the vacuum of the storage vial. Thesolution should not be shaken. Once used, remaining toxin, vial, needlesand syringes should be disposed of in a manner appropriate forbiohazardous waste.

Typical injection technique involves the use of a short, narrow needle(e.g. ½ inch or 8 mm; 30-gage) with an insulin or tuberculin typesyringe. Patients are typically treated in the seated position. The skinarea is cleaned with an alcohol swab. A single syringe may be used formultiple injections to treat different locations in a single muscle ordifferent locations on a patient's face. Typically, the plunger of thesyringe is depressed as the needle is withdrawn so that toxin is evenlydistributed at the injection site. Pressure or gentle massage may beapplied at the injection site to assist in dissipating the toxin. Thetoxin will typically migrate approximately 1 cm from the site ofinjection.

Electromyographic (EMG) guided needles may be used for injection todetermine needle location of a high degree of accuracy, although thistechnique is generally not necessary nor is it required in the instantinvention.

In prior applications of BTX, total dose per treatment is variable andis largely dependent upon the condition being treated and the site ofapplication of BTX. For example, a total dose of 20-30 Units willtypically be applied to the glabellar complex and 60-75 Units forplatysmal bands (c.f. A. Carruthers and J. Carruthers (1998) History ofthe Cosmetic Use of Botulinum A Exotoxin; Dermatol. Surg. 24:1168-1170). Doses of up to 200 Units per treatment session for theplatysma have been reported (Brandt and Bellman [supra]). In priorapplications, a typical dose at a single injection point isapproximately 5 Units of toxin in a 100 Unit/ml dilution.

Onset of muscle paralysis following injection usually occurs withinhours of treatment. The duration of paralysis will vary from patient topatient. Typically, duration will be from 2-8 months before subsequenttreatment is required to alleviate the condition.

This invention provides a successful treatment of Marionette lines and“sad mouth” by BTX injection into the DAO. In such treatment, theorbicularis oris muscle surrounding the mouth is normally avoided inview of its sensitivity to BTX. However, the orbicularis oris muscle maybe treated in conjunction with this invention to alleviate severe upperlip lines or wrinkles. In such a case, a small amount of BTX is injectedinto the orbicularis oris, with the total dose being in the order of 4Units for the entire upper lip. In general, care must be used in BTXtreatments close to the mouth because of the danger of producing aflaccid cheek, an incompetent mouth, or an asymmetric smile.

The DAO may be found by instructing the patient to voluntarily andforcibly pull down the corners of the mouth. The DAO can be then felt bypulling inferiorly at a point approximately 1 cm lateral and 8 mminferior to the commissure. Alternatively, EMG localization may beperformed.

Treatment should take into consideration the pre-existing symmetry ofthe mouth and is performed on both sides of the face in order to providea symmetric result. The required dosage to each side of the mouth shouldbe judged and if necessary, altered upon re-treatment.

Injection may be made into any part of the DAO musculature. Theinjection is intramuscular and may be performed using the injectiontechniques used for other BTX treatments as described above. On atypical patient's face, the preferred point of injection into the DAOwill be approximately 7 mm laterally and 8 mm inferior from the cornerof the mouth. A single injection will usually suffice with the dosagefor a single DAO muscle ranging from 3(±10%) Units-5(±10%) Units. Thebest dose will depend upon the sex of the patient and size of theindividual. Typical doses for a female will be 2(±10%) Units-3(±10%)Units for one side of the mouth; and, for a male, 3(±10%) Units 5(±10%)Units for one side of the mouth.

Contraindications for the use of BTX are known in the art and includechildren under 12, pregnancy, lactation, history of neuromusculardisease and known sensitivity to BTX or human albumin. This invention isnot be recommended for patients who are singers, musicians and otherindividuals who use their perioral muscles with intensity. However,treatment according to this invention will normally not affect normalspeech, whistling or mastication particularly in cases where theorbicularis oris is not treated.

Following application of this invention, laser resurfacing techniquesmay be employed to enhance the effect. In the case of very deepMarionette lines, performance of this invention may be followed by softtissue filling treatment such as collagen, Hylafor™, Restlyane™ (softform) or Gore-Tex™ implants.

The drawings may be referred to for illustration of performance of thisinvention. FIG. 1 shows the location of various facial muscles andanatomical locations referred to herein, including: the DAO 1;orbicularis oris 2; zygomaticus 3; and, the modeolus 4. The platysma,which overlies the neck muscles and extends in part, to region 5, is notillustrated in FIG. 1.

In FIG. 2, region(s) 6 bounded by dashed lines illustrate the generallocation on the patient's skin which overly the DAO. Suitable injectionsites include the areas within region(s) 6 that are marked with a “X”.

All publications referred to herein are hereby incorporated byreference. While the following claims are intended to recite thefeatures of the invention, it will be apparent to those of skill in theart that certain changes may be made without departing from the scope ofthis invention.

We claim:
 1. A method of alleviating downturn of corners of a patient'smouth comprising: b) locating a depressor anguli oris (DAO) muscleadjacent each corner of said mouth; and c) injecting into a DAO adjacenteach corner of the mouth, a quantity of Botulnum toxin (BTX) sufficientto cause paralysis of a DAO.
 2. The method of claim 1 wherein thequantity of BTX injected into each DAO is about 3-5 Unit equivalents. 3.The method of claim 2 wherein the BTX is Botulinum-A toxin.
 4. Themethod of claim 1 wherein the quantity of BTX injected into each DAO isadjusted to compensate for symmetry of the mouth.